What is development?

Development occurs either embryonically or postembryonically.
Embryonic development is when cells differentiate into specific cell types from
more unspecific precursors, and, as they do so, these cells form new tissues and organs.
This occurs in humans within the womb of a mother. Postembryonic development
is any type of developmental changes that occur after one is born. For example,
growing taller and going through puberty.

In this web page, you are going to learn about both embryonic and
postembryonic development of bone. You will see how bone forms within the embryo,
and then also how it continues to be able to grow in length and diameter as we mature.
Next semester, when we discuss hormones (endocrinology), you will see how our bones
can be stimulated to grow more rapidly under the influence of the sex hormones that abound
during puberty.

Embryonic Development of bone

Ossification is the term for the formation of bone.
There are two ways that bone can ossify during embryonic development. Each
way has its own name: intramembranous ossification and endochondral
ossification. Because of these two ways that bone can develop, two types of
bone can be described to exist based on the way they developed embryonically: intramembranous
bones and endochondral bones. The intramembranous bones
are always flat bones, but the endochondral bones include the long, short, and
irregular bones.

I mentioned in lab how most bones start off as cartilage and then
that cartilage is replaced by bone-- that is endochondral ossification. I think it
is easier to understand bone development by starting with intramembranous ossification,
and then progressing to endochondral ossification. So the first type of bone
development that you read about will be completely new to you.

Intramembranous Ossification

Our flat bones, like those of our skull, develop by intramembranous
ossification. If you think for a second about what the word
"intramembranous" means literally, you should realize that it means within
(intra-) membranes (-membranous). So, bones are going to develop within membranes.
That's exactly how this type of bone development occurs.

Connective tissue forms in sheets at sites where flat bones
(intramembranous bones) will eventually be. These connective tissue sheets are
highly invested with blood vessels. Some of the cells in the connective tissue
sheets differentiate into osteoblasts.

Terminology note: differentiation is when a cell takes on a specific
cellular identity during development... in the above sentence, it is when a
fibroblast-like cell becomes an osteoblast, instead of further differentiating into a
fibroblast. Keep in mind that when embryonic development starts, we are all
made up of only one cell. This one cell has to make trillions of cells, with many
different identities.

Back to intramembranous ossification... Now we have connective
tissue sheets which contain osteoblasts within them. These osteoblasts begin laying
down the bone extracellular matrix, forming spongy bone. These osteoblasts get
trapped within the hard matrix and are then called osteocytes. When they have done
this, we now have a sandwich where the connective tissue sheets are the bread and the
spongy bone is the meat. This forms the basis from which the bone will finish
developing. It is not done developing, because even flat bone is made up of both
spongy and compact bone. At this point we haven't made any compact bone yet-- that
is our next task.

There are more and more osteoblasts forming from the connective
tissue sheets as time goes on. The connective tissue sheets, as they become major
producers of osteocytes, are no longer simply called connective tissue sheets. They
are now called the bone's periosteum. But the newer osteoblasts made by the
periosteum cannot enter the spongy bone. So, instead, they begin to accumulate on
the edges of the spongy bone. There, they lay down more hard matrix, but now as
compact bone. Then, they get trapped within this matrix and are called osteocytes.

We have now finished making our intramembranous bone. I have
tried to create a little movie to show you the main points above. I hope it helps!

Endochondral Ossification

In endochondral ossification, bone forms by replacing hyaline
cartilage. As I mentioned in lab, the embyronic skeleton, early on, is mainly made
up of hyaline cartilage (except for flat bones). At some point, endochondral
ossification begins, and starts replacing the cartilage with bone. The cartilage is
considered to simply be a "model" for the shape the bone should take on, and so
it is often referred to as a "cartilaginous model."

The way it works is that the chondrocytes within the cartilaginous
model begin to die. Chondrocytes are seen to swell up as they die, so if you see
swollen chondrocytes, you can pretty much know that they are on their way toward death.
At the same time that this is occurring, a periosteum is forming around the outside
of the cartilaginous model. This periosteum will supply the needed osteoblasts for
bone development.

Where along the cartilaginous model do the chondrocytes begin to
die? Well, first, they begin to die right in the middle of the diaphysis. This
region becomes known as the primary ossification center. After this
gets underway, the next round of chondrocyte death occurs within the epiphyses, and these
regions are called secondary ossification centers. Take a look at
figure 7.8 on page 190 to follow along with the notion of these two ossification centers.
Do you see that even when they are done making the bone, the primary and secondary
ossification centers never merge? They always remain separate. That ends up
leaving a little bit of cartilage between the diaphysis and the epiphyses...

Now think back to the bone structure page... what is found to
lie between the diaphysis and the epiphyses??? The epiphyseal disks.
Therefore, you should now understand that the epiphyseal disks are disks of hyaline
cartilage within bone. This is important to know before you can learn about how
bones grow. To see what this really looks like, visit this Univ of Wisc Anatomy web page
and select slide number 49 (choose the "L" for the labeled image).

Well, now that you know where chondrocyte death occurs, lets
follow the bone formation from there. As the chondrocytes die, the model is not so
tough any more, and blood vessels, nerves, and osteoblasts can invade. They dive in
and the osteoblasts begin to do what they do best-- secrete hard extracellular matrix
material. They do this until they get trapped inside it as osteocytes. This
initial ossification forms spongy bone. Therefore, the cartilage of the diaphysis
and then the epiphyses gets replaced by spongy bone.

Meanwhile, the periosteum is still producing osteoblasts.
Eventually they cannot enter the spongy bone region anymore, so they start building up
along the outside edges (everywhere except for on the tips of the epiphyses where hyaline
cartilage remains as the articular cartilage). As the osteoblasts build up on the
periphery of the spongy bone, they secrete their matrix and build compact bone all around
the spongy bone.

I did not make a little video of this. It was a bit
time-consuming to do the first one (3 hours!), so I thought I should stop while I was
ahead. But, do you understand how it happens? Try to draw out the steps
yourself-- your book draws it out at the macroscopic level... you can try it at the
microscopic level: step-by-step.

From the Loyola University Medical Education Network, abbreviated LUMEN, you
can click on Part 10: endochondral ossification and see a lengthy series of images
of this type of bone development.

Finally, how do the medullary cavities wind up present in bone?
Well, another cell type, that I describe in detail below, comes in and cleans out
the spongy bone from the middle of the diaphysis. That leaves a cavity, which gets
filled with marrow.

Postembryonic development of bone (bone growth)

Bones need to grow longer in order for us to get taller, but they
also need to grow wider in order to have more girth to physically support our larger size.
Of these two ways of growing, growing in width is the easiest to understand, so
I'll start there.

Widening growth of bone

In order for bone to grow wider, all that has to happen is that more
compact bone must be laid down around the periphery (outside edge) of the bone. You
should already be able to figure out how that must happen. The peripheral edge of
bone is lined by periosteum; this membrane can continue to form osteoblasts.
Therefore, more osteoblasts form and are deposited directly underneath the
periosteum. These new osteoblasts secrete more matrix and get caught inside it as
osteocytes, and...

...voila!

More compact bone has been deposited on the periphery of the bone, so our bone is
wider!

Lengthening growth of bone

Long bones need to get longer for us to grow taller. The way
they do this is a modification of the way that they develop embryonically-- they replace
cartilage with bone. This is a type of endochondral ossification, but it can also
occur postembryonically. The only cartilage that remains within bone is that
cartilage that is found in the epiphyseal disks. Therefore, that is the cartilage
that they replace. But you should see one little flaw in my logic...

... if you replace the cartilage of the epiphyseal disks with bone,
you lose the epiphyseal disks entirely and will not have them to continue to grow.
Do you see that?

Therefore, the cartilage within the epiphyseal disks is continually
dividing (sometimes faster than other times)... as it makes more cartilage, the older
cartilage is replaced by bone. That is the quick-and-dirty way to understand bone
growth. However, we can get much more specific than that by looking more closely at
what is happening at the cellular (microscopic) level.

Take a look at Figure 7.9 in your textbook. Also, I have
inserted a figure here from the LUMEN web site.
Next to it you'll see an edited version of their figure legend.

"Endochondral ossification in greater detail. The cartilage
cells (chondrocytes) near the region of active ossification have enlarged (hypertrophied)
and lined up more or less in columns. The purplish material in the center of the shaft is
primitive bone marrow, with reticular cells and developing blood cells. The vascular
elements of the marrow tissue actively invade the cartilage above, leaving spicules of
calcified cartilage, upon which bony matrix will be deposited. The dark pink spicules here
are made of bone; the paler pink, small spicules at the leading edge of the cartilage are
made of calcified cartilage."

What I'd like you to note is that the left half of the photo is the
epiphyseal disk. The lightest band running up and down within that is the region of
the epiphyseal disk where things are taking place, like cell death and replacement by
bone. The area to the left of this lightest area, running up and down above the
"LUMEN" logo, is where the cartilage remains undamaged within the epiphyseal
disk. This photo is from when the epiphyseal disk is still a bit big-- it
hasn't finished forming yet, but the points you can see within it are still pretty clear.

The right half of the photo above (and the bottom of Figure 7.9 in
your book) is from where bone is (of the diaphysis). In order for the bone to grow
in length, it has to grow toward the left above (or upward in your textbook). So,
the bone is going to take over and replace the cartilage that is immediately next to it.
Osteoblasts can only lay down new bone if they can get into the area where they
need to do it.

So, the cartilage at the far left is constantly dividing, and making
more chondrocytes. The older cells, where it is starting to get lighter in the
figures, are beginning to swell... then, farther to the right where it is even lighter,
they die. Once the chondrocytes are dead, the osteoblasts can come in and lay down
new bone.

We can describe this process in four layers within the epiphyseal disk:

chondrocytes that remain undamaged and unbothered ("resting cells" is how they
are described in your textbook)

dividing chondrocytes. The activity of these chondrocytes ensures that the
epiphyseal disk will not get used up quickly.

Dying chondrocytes (these are swelling up)

Dead chondrocytes (just their extracellular matrix remains)

There are still some important points that I have skipped over to make this easier to
understand...

When the chondrocytes die during bone lengthening, their extracellular matrix gets very
tough. The reason is that it gets loaded with calcium salts, which make it harder.
This hardening process is called calcification.

In order for the osteoblasts to be able to get into the region of dead chondrocytes,
they have to get through the calcified cartilaginous matrix. They cannot.
Therefore, yet another type of cell, the osteoclast, is enlisted to
help. The osteoclast is specialized in endocytosis-- taking in and chewing up
material that is around it. These cells are derived from the blood; a certain type
of blood cell, the monocyte, differentiates into osteoclasts in bone. Therefore, the
osteoclasts clear the way for the invasion of osteoblasts.

The epiphyseal disk doesn't remain hearty forever. When we are finished with
puberty we stop growing because our hormones cause all of the cartilage within the
epiphyseal disks to become ossified. You'll learn about this more next semester when
we do the endocrine system.